ASYMMETRIC ALKYLATIONS OF A PHENYLALANYLGLYCINATE EQUIVALENT - NOVEL ROUTE TO DIPEPTIDES BEARING ALPHA-ALKYL-ALPHA-AMINO ACID RESIDUES

Asymmetric single and double alkylations of chiral β-lactam acetate 1, which is a chiral glycinate as well as a phenylalanylglycinate equivalent, are studied. First, the sequential asymmetric double alkylation of 1a is performed to give the corresponding doubly alkylated β-lactam esters 3 (>99% de) in high yields, which can readily be converted to the corresponding dipeptides (4) via dissolving metal reduction in good yield. The salient advantage of this method is that a quaternary chiral center of desired configuration can be created just by changing the order of the addition of two alkyl halides used (R1 ≠ R2). Remarkable effect of temperature on stereoselectivity is observed in the asymmetric single alkylation of 1a, e.g., in the lithium enolate formation and alkylation of 1a with allyl bromide; the observed stereoselectivities (R/S) are 7.6/1 at-95 °C, >50/1 at-78 °C, 7.9/1 at-50 °C, and 4.4/1 at-30 °C. Similar dependence of stereoselectivity on the reaction temperature is also observed for the reactions with methyl iodide and benzyl bromide. When ethyl bromoacetate was used as an electrophile, the reaction gave the highest stereoselectivity at-97 °C (>50/1) rather than at-78 °C, and the stereoselectivity decreased along with the increase of temperature. A rationale for the observed effect of temperature on stereoselectivity is proposed. The single alkylation products can be readily converted to the corresponding dipeptides through dissolving metal reduction and then to amino acids by hydrolysis; hence this asymmetric single alkylation serves as a new and effective method for the synthesis of enantiomerically pure non-protein amino acids and their dipeptides. Finally, the sequential asymmetric triple alkylation of 1a with methyl iodide, allyl bromide, and methyl iodide is successfully achieved to give 5a-1 with virtually complete stereoselectivity. Deprotection of the tert-butyl ester of 5a-1 followed by the cleavage of ²-lactam ring as well as the removal of (V-protection with Li/NH3/THF/t-BuOH at-78 °C gave enantiomerically pure (S)-°-methylphenylalanyl-(R)-°-allylalanine (6a-1) after purification on an ion-exchange column. © 1990, American Chemical Society. All rights reserved.